8-azabicyclo(3,2,1)oct-2-ene and octane derivatives as cholinergic ligands at nicotinic ACh receptors

ABSTRACT

The present invention discloses compounds of formula (1) any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein  - - - -  is a single or a double bond; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,                    
     cycloalkylalkyl, aryl or aralkyl; and R 1  is (a), wherein R 2  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino; or aryl which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalklyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF 3 , OCF 3 , CN, amino, aminoacyl, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group; a monocyclic 5 to 6-membered heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF 3 , OCF 3 , CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group; or a bicyclic heteroaryl group composed of a monocyclic 5 to 6 membered heteroaryl group fused to a benzene ring or fused to another monocyclic 5 to 6-membered heteroaryl, all of which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy methylenedioxy, aryloxy, halogen, CF 3 , OCF 3 , CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group. The compounds of the invention are useful as nicotinic ACh receptor ligands.

This application is a Continuation of PCT International Application No.PCT/DK98/00225 filed on May 29, 1998, which designated the UnitedStates, and on which priority is claimed under 35 U.S.C. §120, theentire contents of which are hereby incorporated by reference.

The present invention relates to novel 8-Azabicyclo[3.2.1]oct-2-ene and-octane derivatives which are cholinergic ligands at nicotinic AChreceptors. The compounds of the invention are useful for the treatmentof condition or disorders or diseases involving the cholinergic systemof the central nervous system, pain, inflammatory diseases, diseasescaused by smooth muscle contractions and as assistance in the cessationof chemical substance abuse.

BACKGROUND

The endogenous cholinergic neurotransmitter, acetyicholine, exert itsbiological effect via two types of cholinergic receptors; the muscarinicACh receptors and the nicotinic ACh receptors. As it is well establishedthat muscarinic ACh receptors dominate quantitatively over nicotinic AChreceptors in the brain area important to memory and cognition, muchresearch aimed at the development of agents for the treatment of memoryrelated disorders have focused on the synthesis of muscarinic AChreceptor modulators. Recently, however, an interest in the developmentof nicotinic ACh receptor modulators has emerged. Several diseases areassociated with degeneration of the cholinergic system i.e. seniledementia of the Alzheimer type, vascular dementia and cognitiveimpairment due to the organic brain damage disease related directly toalcoholism. Indeed several CNS disorders can be attributed to acholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency or a serotonergic deficiency. Alzheimer's disease ischaracterised by a profound loss of memory and cognitive functionscaused by a severe depletion of cholinergic neurons, i.e. neurons thatrelease acetyicholine. A reduction in the number of nicotinic AChreceptors are also observed with the progression of Alzheimer's disease.It is believed that the neurons in the cortex that die with theprogression of Alzheimer's disease do so because of lack of stimulationof the nicotinic ACh receptors. It is predicted that treatment ofAlzheimer's patients with nicotinic ACh receptor modulators will notonly improve the memory of patients but in addition act to keep theseneurons alive. Smoking actually seems to protect individuals againstneurodegeneration and compounds behaving on these receptor may verylikely have a generally neuroprotective effect.

However degeneration of the cholinergic system is not limited toindividuals suffering from i.e. Alzheimers disease but is also seen inhealthy aged adults and rats. Therefore it is suggested that thecholinergic system is involved and partly responsible for the memorydisturbances seen in aged animals and humans. Nicotine receptormodulator may therefore be useful in the treatment of Alzheimer'sdisease, memory loss, memory dysfunction, AIDS-dementia, senile dementiaor neurodegenerative disorders.

Parkinsons disease appears to involve degeneration of dopaminergicneurons. One symptom of the disease has been observed to be loss ofnicotinic receptors associated with the dopaminergic neurons andpossibly interfering with the process of release of dopamine. Assustained nicotine administration increases the number of receptorspresent, administration of nicotine receptor modulators may amelioratethe symptoms of Parkinson's disease. Other condition or disorders ordisease ascribed to deficiencies in the dopaminergic system is: drugaddiction, depression, obesity and narcolepsy.

Tourette's syndrome is a neuropsychiatric disorder involving a range ofneurological and behavioral symptoms. It is believed thatneurotransmitter dysfunction is involved though the pathophysiology isstill unknown and that nicotine will be beneficial in the treatment ofthe disease (Devor et. al. The Lancet, vol. 8670 p. 1046, 1989)

Schizophrenia is a severe psychiatric illness. Neuroleptic compounds hasbeen used in the treatment of the disease, the effect of the compoundsis believed to be interaction in the dopaminergic system. Nicotine isproposed to be effective in the treatment of schizophrenia (Merriam et.al. Psychiatr. annals, Vol. 23, p. 171-178,1993 and Adler et. al. Biol.Psychiatry, Vol. 32, p. 607-616, 1992.)

Nicotine has been reported to have en effect on neurotransmitter releasein several systems. Release of acetylcholine and dopamine by neuronsupon administration of nicotine has been reported (J. Neurochem. vol.43, 1593-1598, 1984) and release of norepinephrine by Hall et. al.(Biochem. Pharmacol. vol. 21, 1829-1838, 1972) Release of serotonin byHery et. al. (Arch. Int. Pharmacodyn. Ther. vol. 296. p. 91-97, 1977).Release of glutamate by Toth et. al (Neurochem. Res. vol. 17, p.265-271, 1992).

The serotonin system and dysfunction's of the serotonergic system isbelieved to be involved in diseases or conditions or disorders like:anxiety, depression, eating disorders, obsessive compulsive disorder,panic disorders, chemical substance abuse, alcoholism, pain, memorydeficits and anxiety, pseudodementia, Ganser's syndrome, migraine pain,bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome,tobacco abuse, post-traumatic syndrome, social phobia, chronic fatiguesyndrome, premature ejaculation, erectile difficulty, anorexia nervosa,disorders of sleep, autism, mutism or trichotillomania.

Nicotine improves concentration and task performance. Thereforecompounds exhibiting nicotine receptor modulating properties will belikely to be useful compounds in the treatment of learning deficit,cognition deficit, attention deficit, attention deficit hyperactivitydisorder and dyslexia.

Tobacco use and especially cigarette smoking is recognised as a serioushealth problem. However nicotine withdrawal symptoms associated withsmoking cessation makes it difficult to break this habit. Withdrawalsymptoms include anger, anxiety, difficulties in concentrating,restlessness, decreased heart rate and increased appetite and weightgain. Nicotine itself has shown to ease the withdrawal symptoms.

Withdrawal from addictive substances, i.e. opiates, benzodiazepines,ethanol, tobacco or nicotine, is in general a traumatic experiencecharacterised by anxiety and frustration. Nicotine has been found to beeffective in reducing anger, irritability, frustration and feelings oftension without causing general response depression, drowsiness orsedation and compounds having same characteristics as nicotine is likelyto have same effects.

Mild to moderate pain is normally treatable with NSAID's (non-steroidalanti-inflammatory drugs) while opiates are used preferentially formoderate to severe pain. The opiates have some well-known side-effects,including chemical dependence and abuse potential as well as adepressive effect on the respiratory and gastrointestinal system. Thereexists therefore a strong need for analgesic compounds that do notexhibit these side effects and which can relieve mild, moderate andsevere pain of acute, chronic or recurrent character as well as migrainepain and postoperative pain, phantom limb pain.

Epibatidine, a compound isolated from the skin of a poison frog, is avery potent analgesic with an approximate potency of 500 times that ofmorphine. The analgesic effect is not affected by naloxone, which is anindication of a negligible affinity for the opiate receptors.Epibatidine is an nicotinic cholinergic receptor agonist and it istherefore very likely, that compounds possessing this receptormodulating character will also show a strong analgesic response. Thecompounds of the present invention has proven useful for modulation ofsmooth muscle contractions and may therefore be used in the treatment orprevention of condition or disorders or diseases inherent from smoothmuscle contractions like i.e. convulsive disorders, angina pectoris,premature labor, convulsions, diarrhoea, asthma, epilepsy, tardivedyskinesia, hyperkinesia.

Further, it is well known that nicotine has an effect on appetite and itis predicted that modulators at the nicotine ACh receptor may be usefulas appetite suppressants in the treatment of obesity and eatingdisorders.

The cholinergic receptors play an important role in the functioning ofmuscles, organs and generally in the central nervous system. There arealso complex interactions between cholinergic receptors and the functionof receptors of other neurotransmitters such as dopamine, serotonin andnoradrenaline.

It is likely that nicotine receptor modulator compounds can be effectivein preventing or treating conditions or disorders or diseases like:inflammation, inflammatory skin conditions,

Chron's disease, inflammatory bowel disease, ulcerative collitis,diarrhoea, neurodegeneration, perpherical neuropathy, amyotrophiclateral sclerosis, nociception, endocrine disorders, thyrotoxicosis,pheochromocytoma, hypertension, arrhytmias, mania, manic depression,Huntington's disease, jetlag.

The compounds of the present invention are nicotine receptor modulatorsand has the potential to exhibit nicotinic pharmacology, preferentiallywithout the side effects associated with nicotine itself. Additionally,the compounds are expected to have the potential as enhancers ofneurotransmitter secretion and suppress symptoms associated with a lowactivity of neurotransmitters.

Structural close analogues to the compounds of the present invention aredescribed in EP 122580 which describes pyrimidine derivatives asdihydrofolate reductase inhibitors useful against bacterial infectionsand malaria.

GB 2298647 describes bridged piperidines which promotes the release ofgrowth hormone.

WO 97/13770 describes monoamine neurotransmitter reuptake inhibitors.

EP 0498331 which describesN-(aryloxyalkyl)-heteroaryl-8-azabicyclo(3.2.1)octanes as antipsychoticagents and as inhibitors of the reuptake of serotonin.

J. Med. Chem. 1995, 38, 1998-2008, describes σ-ligands with potentialanxiolytic activity.

J. Org. Chem. 1994, 59, 2164-2171, describes abbreviated Ibogainecongeners.

There is thus a large need for the development of nicotinic ACh receptormodulators with a more favourable pharmacological profile. A favourablepharmacological profile meaning for example:

A high binding selectivity for the receptor subtypes of neuronalnAChR's, e.g. the α7-subtype

A low affinity for the muscular subtype.

An induction of cell survival.

An oral efficacy in vivo (rat model) of arousal/attention.

A low toxicity in vivo.

A non-mutagenic compound

According to the present invention valuable modulators of the nicotiniccholinergic receptors are provided. Certain compounds which areantagonists at the nicotinic ACh receptor may be useful for thetreatment of transient anoxia and induced neurodegeneration.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel8-Azabicyclo[3.2.1]oct-2-ene and -octane derivatives which are usefulfor the treatment of a range of diseases or conditions or disorderscharacterised by decreased cholinergic function or responsive to theactivity of nicotinic ACh receptor modulators.

Another object of the present invention is to provide novelpharmaceutical compositions containing these compounds, as well asmethods for the preparation thereof and methods for the treatmenttherewith.

It is yet another object of the invention to provide novel compoundsthat have some if not all of the following favourable characteristics:

A high binding selectivity for the receptor subtypes of neuronalnAChR's, e.g. the α7 subtype.

A low affinity for the muscular subtype.

An induction of cell survival.

An oral efficacy in vivo of arousal/attention.

A low toxicity in vivo.

A non-mutagenic compound.

Other objects will become apparent hereinafter to one skilled in theart.

THE PRESENT INVENTION

In the context of this invention “treating” covers treatment,prevention, profylaxis or alleviation and “disease” covers a disease ora disorder or a condition; In the context of this invention “modulator”covers agonists, partial agonists, antagonists and allostericalmodulators.

In the context of this invention disorders in the central nervous systemcovers for example: neurodegenerative disorders, cognitive or memorydysfunction, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, Amyotrophic Lateral Sclerosis, Gilles de la Tourettes syndrome,attention deficit hyperactivity disorder, anxiety, depression, mania,manic depression, schizophrenia, obsessive compulsive disorders, eatingdisorders like anorexia nervosa, bulimia and obesity, narcolepsy,nociception, memory loss, memory dysfunction, AIDS-dementia, seniledementia, peripherial neuropathy, learning deficit, cognition deficit,attention deficit, autism, dyslexia, tardive dyskinesia, hyperkinesia,epilepsy, bulimia, post-traumatic syndrome, social phobia, chronicfatigue syndrome, disorders of sleep, pseudodementia, Ganser's syndrome,prementraul syndrome, late luteal phase syndrome, chronic fatiguesyndrome, premature ejaculation, erectile difficulty, mutism andtrichotillomania.

In the context of this invention inflammatory conditions covers forexample: inflammatory skin conditions like acne and rosacea, Chron'sdisease, inflammatory bowel disease, ulcerative collitis, diarrhoea.

Diseases associated with smooth muscle contractions covers for example:convulsive disorders, angina pectoris, premature labor, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

In the context of this invention pain covers for example chronic, acuteand recurrent pain, postoperative pain, migraine pain or phantom limbpain;

Abuse of chemical substances covers smoking as well as use of othernicotine containing products, use of opiods like heroin, cocaine andmorphine, use of benzodiazepines or alcohol. In this context “treatment”covers treatment, prevention, profylaxis and alleviation of withdrawalsymptoms and abstinence as well as treatment resulting in a voluntarydiminished intake of the addictive substance.

The invention then, inter alia, comprises the following, alone or incombination:

A compound having the formula,

any of its enantiomers or any mixture thereof, or a pharmaceuticallyacceptable salt thereof;

wherein

- - - - is a single or a double bond;

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl or aralkyl; and

 wherein R² is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, amino; or

aryl which may be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy,methylenedioxy, aryloxy, halogen, CF₃, OCF₃, CN, amino, aminoacyl,nitro, aryl and a monocyclic 5 to 6 membered heteroaryl group;

a monocyclic 5 to 6 membered heteroaryl group which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy,cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy,halogen, CF₃, OCF₃, CN, amino, nitro, aryl and a monocyclic 5 to 6membered heteroaryl group; or

a bicyclic heteroaryl group composed of a monocyclic 5 to 6 memberedheteroaryl group fused to a benzene ring or fused to another monocyclic5 to 6 membered heteroaryl, and which may be substituted one or moretimes with substituents selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy,thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF₃,OCF₃, CN, amino, nitro, aryl and a monocyclic 5 to 6 membered heteroarylgroup;

A preferred embodiment of the invention is a compound of formula 1wherein

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl or aralkyl; and

 wherein R²is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, amino; or

aryl which is substituted one or more times with substituents selectedfrom the group consisting of cycloalkyl, cycloalkylalkyl alkenyl,alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy,methylenedioxy, aryloxy, OCF₃, CN, amino, aminoacyl, nitro, aryl and amonocyclic 5 to 6 membered heteroaryl group;

a monocyclic 5 to 6 membered heteroaryl group which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy,cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy,halogen, CF₃, OCF₃, CN, nitro, aryl and a monocyclic 5 to 6 memberedheteroaryl group; or

a bicyclic heteroaryl group composed of a monocyclic 5 to 6 memberedheteroaryl group with one heteroatom, fused to a benzene ring or fusedto another monocyclic 5 to 6 membered heteroaryl, all of which may besubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl,alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy,aryloxy, halogen, CF₃, OCF₃, CN, amino, nitro, aryl and a monocyclic 5to 6 membered heteroaryl group;

Another preferred embodiment of the invention is compound of formula 1wherein

R is hydrogen, methyl, ethyl or benzyl;

R¹ is acetyl, 2-methoxyphenyl, 2-naphtyl, 3-acetamidophenyl,2-selenophenyl 3-pyridyl, 3-(6-methoxy)pyridyl, 3-(6-chloro)pyridyl,2-thiazolyl, 3-thienyl, 2-thienyl, 2-methoxymethyl)thienyl, 2-furyl,3-furyl, 2-(3-bromo)thienyl), 3-chloro-thien-2-yl, 3-(3-furyl)2-thienyl,3-quinolinyl, 3-benzofuryl, 2-benzofuryl, 3-benzothienyl,2-benzothienyl, 2-benzothiazolyl, 2-thieno[3.2-b]thienyl,thieno[2.3-b]thienyl, 2-(3-bromo)benzofuryl or 2-(3-bromo)benzothienyl;

A further embodiment of the invention is a compound as above which is

(±)-8-Benzyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-(3-quinolinyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(3-Benzofuryl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(3-Benzothienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Thiazolyl)-8-Methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-(3-thienyl)-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-(2-naphtyl)-8-azabicyclo[3.2.1]oct-2-ene;

Exo-8-Methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]octane;

(±)-8-H-3-(3-Pyridyl)-B-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-[3-(6-methoxy)-pyridyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-Acetyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-[3-(6-chloro)-pyridyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Benzofuryl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Benzothienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(3-Acetamidophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(3-Aminophenyl) 8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Thienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Methoxymethylthienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Benzothiazolyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Furyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Thieno[3.2-b]thienyl)-8-methyl-8azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Thieno[2.3-b]thienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Selenophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Benzofuryl)-8-H-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(3-Furyl)-2-thienyl]-8-H-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-(2-Benzofuryl)-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromobenzofuryl)]-8-methyl-8-azabicyclo[3.2.1)oct-2-ene;

(±)-3-[2-(3-Bromobenzothienyl)]-8-methyl-8-azabicyclo[3.2.1)oct-2-ene;

3-[2-(3-Chlorothienyl)]-8-methyl-8-azabicyclol3.2.1]oct-2-ene or

(±)-3-[3-(3-Furyl)-2-thienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

or a pharmaceutically acceptable addition salt thereof;

a pharmaceutical composition, comprising a therapeutically effectiveamount of a compound as above, or a pharmaceutically acceptable additionsalt thereof, together with at least one pharmaceutically acceptablecarrier or diluent;

the use of a compound as above for the manufacture of a medicament forthe treatment or prevention of a condition or disorder or disease of aliving animal body, including a human, which condition or disorder ordisease is responsive to the activity of nicotinic ACh receptormodulators;

the use of a compound as above wherein the disease to be treated ispain, a disease in the central nervous system, a disease caused bysmooth muscle contraction, neurodegeneration, inflammation, chemicalsubstance abuse or withdrawal symptoms caused by the cessation of intakeof the chemical substance.

The use as above wherein the disease is a disease in the central nervoussystem said disease being Alzheimer's disease, Parkinson's disease,memory dysfunction or attention deficit hyperactivity disorder.

The use as above wherein the disease to be treated is chemical substanceabuse or withdrawal symptoms caused by the cessation of intake of thechemical substance, said chemical substance abuse being smoking or useof other nicotine containing products and withdrawal symptoms caused bycessation of use of nicotine containing products;

a method for the preparation of the compounds as above comprising thestep of reacting a compound having the formula

a) the step of reacting a compound having the formula

wherein R is as defined above, with a compound of the formula R¹—Li,wherein R¹ is as defined above followed by dehydration of the compoundobtained;

b) the step of reacting a compound having the formula

wherein R is as defined above, with a compound of formula R¹—X, whereinR¹ is as defined above and X is halogen, boronic acid, ortrialkylstannyl; or

c) the step of reducing a compound having the formula

wherein R¹ is as defined above;

a method of treating a disease of a living animal body, including ahuman, which disease is responsive to the activity of nicotinic AChreceptor modulators, comprising the step of administering to such aliving animal body, including a human, in need thereof a therapeuticallyeffective amount of a compound as above;

the method as above wherein pain, a disease of the central nervoussystem, neurodegeneration, inflammation, chemical substance abuse,withdrawal symptoms from cessation of use of addictive substances, or adisease caused by smooth muscle contractions is treated;

The method as above wherein chemical substance abuse or withdrawalsymptoms caused by the cessation of intake of the chemical substance,said chemical substance abuse being smoking or use of other nicotinecontaining products and withdrawal symptoms caused by cessation of useof nicotine containing products, is treated;

The method as above wherein a disease in the central nervous system,said disease being Alzheimer's disease, Parkinson's disease, memorydysfunction or attention deficit hyperactivity disorder, is treated;

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate,maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate,benzenesulfonate, methanesulfonate, stearate, succinate, glutamate,glycollate, toluene-p-sulphonate, formate, malonate,naphthalene-2-sulphonate, salicylate and the acetate. Such salts areformed by procedures well known in the art.

Other acids such as oxalic acid, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of one to six carbonatoms, including but not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, and hexyl; methyl, ethyl, propyl andisopropyl are preferred groups.

Cycloalkyl means cyclic alkyl of three to seven carbon atoms, includingbut not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

Alkenyl means a group of from two to six carbon atoms, including atleast one double bond, for example, but not limited to ethenyl, 1,2- or2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.

Alkynyl means a group of from two to six carbon atoms, including atleast one triple bond, for example, but not limited to ethynyl, 1,2- or2,3-propynyl, 1,2- or 2,3- or 3,4-butynyl.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy is O-cycloalkyl, wherein cycloalkyl is as defined above.

Thioalkoxy is S-alkyl, wherein alkyl is as defined above.

Thiocycloalkoxy is S-cycloalkyl, wherein cycloalkyl is as defined above.

Amino is NH₂ or NH-alkyl or N-—alkyl)₂, wherein alkyl is as definedabove.

Acyl is (C═O)—R^(o) or (C═S)—R^(o) wherein R^(o) is alkyl, alkoxy, arylor aryloxy; wherein alkyl and alkoxy is defined above and aryl andaryloxy is defined below;

Aminoacyl is —NH-acyl, wherein acyl is defined above;

A monocyclic 5- to 6-membered heteroaryl group containing one, two,three or four heteroatomes and includes, for example, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol4-yl, 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyland 3-pyrazinyl and 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl,tetrazolyl.

A bicyclic heteroaryl group composed of a 5 to 6 membered monocyclicheteroaryl group and a fused benzene ring or another 5 to 6 memberedmonocyclic heteroaryl group, means a monocyclic 5 to 6 memberedheteroaryl group as above which is fused to a benzene ring or fused to a5 to 6 membered heteroaryl as above, including, for example,

2-, 3-, 4-, 5-, 6-, 7-benzofuranyl, 1-, 2-, 4-, 5-benzimidazolyl, 2-,3-, 4-, 5-, 6-, 7-indolyl, 2-,3-,4-,5-,6-,7-,8-quinolinyl and1-,3-,4-,5-,6-,7-,8-isoquinolinyl, thieno[3,2-b]thienyl,thieno[2,3-b]thienyl;

Aryl is an aromatic hydrocarbon, such as phenyl and naphthyl.

Aryloxy is —O-aryl where aryl is defined above.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

It will be appreciated by those skilled in the art that the compounds ofthe present invention contain several chiral centres and that suchcompounds exist in the form of isomers (i.e. enantiomers). The inventionincludes all such isomers and any mixtures thereof including racemicmixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallization of d- or l- (tartrates, mandelates, orcamphorsulphonate) salts for example. The compounds of the presentinvention may also be resolved by the formation of diastereomeric amidesby reaction of the compounds of the present invention with an opticallyactive activated carboxylic acid such as that derived from (+) or(−)phenylalanine, (+) or (−)phenylglycine, (+) or (−)camphanic acid orby the fornation of diastereomeric carbamates by reaction of thecompounds of the present invention with an optically activechloroformate or the like.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage worker skilled in the art. Such methods include those discussedby J. Jaques, A. Collet, and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

The compounds of the invention may be prepared by any conventionalmethod useful for the preparation of analogous compounds and asdescribed in the examples below.

Starting materials for the processes described in the present patentapplication are known or can be prepared by known processes fromcommercially available materials

A compound of the invention can be converted to another compound of theinvention using conventional methods.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallisation, distillation,chromatography, and the like.

BIOLOGY

Nicotinic ACh receptors in the brain are pentameric structures composedof subunits distinct from those found in skeletal muscles. The existenceof eight α-subunits (α2-α9) and three β-subunits (β2-β4) in themammalian brain has been described.

The predominant subtype with high affinity for nicotine is comprised ofthree α₄ and two β₂ subunits.

The affinity of compounds of the invention for nicotinic ACh receptorshave been investigated in three test for in vitro inhibition of³H-epibatidin binding, ³H-α-bunga-rotoxin binding and ³H-cytisinebinding as described below:

In vitro inhibition of ³H-cytisine binding

The predominant subtype with high affinity for nicotine is comprised ofα₄ and β₂ subunits. nAChRs of the latter type can selectively belabelled by the nicotine modulator ³H-cytisine.

Tissue Preparation: Preparations are performed at 0-4° C. unlessotherwise indicated. Cerebral corticies from male Wistar rats (150-250g) are homogenised for 20 sec in 15 ml Tris, HCl (50 mM, pH7.4)containing 120 mM NaCl, 5 mM KCl, 1 mM MgCl₂ and 2.5 mM CaCl₂ usingan Ultra-Turrax homogeniser. The homogenate is centrifuged at 27,000×gfor 10 min. The supernatant is discarded and the pellet is resuspendedin fresh buffer and centrifuged a second time. The final pellet isresuspended in fresh buffer (35 ml per g of original tissue) and usedfor binding assays.

Assay: Aliquots of 500 μl homogenate are added to 25 μl of test solutionand 25 μl of ³H-cytisine (1 nM, final concentration), mixed andincubated for 90 min at 2° C. Non-specific binding is determined using(−)-nicotine (100 μM, final concentration). After incubation the samplesare added 5 ml of ice-cold buffer and poured directly onto Whatman GF/Cglass fibre filters under suction and immediately washed with 2×5 mlice-cold buffer. The amount of radioactivity on the filters isdetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding.

In vitro Inhibition of ³H-α-Bungarotoxin Binding Rat Brain

α-Bungarotoxin is a peptide isolated from the venom of the Elapidaesnake Bungarus multicinctus (Mebs et al., Biochem. Biophys. Res.Commun., 44(3), 711 (1971)) and has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.³H-α-Bungarotoxin binds to a single site in rat brain with an uniquedistribution pattern in rat brain (Clarke et al., J. Neurosci. 5,1307-1315 (1985)).

³H-α-Bungarotoxin labels nAChR formed by the ca subunit isoform found inbrain and the α₁ isoform in the neuromuscular junction (Changeaux, FidiaRes. Found. Neurosci. Found. Lect. 4, 21-168 (1990). Functionally, theα₇ homo-oligomer expressed in oocytes has a calcium permeability greaterthan neuromuscular receptors and, in some instances greater than NMDAchannels (Seguela et al., J. Neurosci. 13, 596-604 (1993).

Tissue preparation: Preparations are performed at 0-4° C. unlessotherwise indicated. Cerebral cortices from male Wistar rats (150-250 g)are homogenised for 10 sec in 15 ml 20 mM Hepes buffer containing 118 mMNaCl, 4.8 mM KCl, 1.2 mM MgSO₄ and 2.5 mM CaCl₂ (pH 7.5) using anUltra-Turrax homogeniser. The tissue suspension is centrifuged at27,000×g for 10 min. The supernatant is discarded and the pellet iswashed twice by centrifugation at 27,000×g for 10 min in 20 ml freshbuffer, and the final pellet is resuspended in fresh buffer containing0.01% BSA (35 ml per g of original tissue) and used for binding assays.

Assay: Aliquots of 500 μl homogenate are added to 25 μl of test solutionand 25 μl of ³H-α-bungarotoxin (2 nM, final concentration), mixed andincubated for 2 h at 37° C. Non-specific binding is determined using(−)-nicotine (1 mM, final concentration). After incubation the samplesare added 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poureddirectly onto Whatman GF/C glass fibre filters (presoaked in 0.1% PEIfor at least 6 h) under suction and immediately washed with 2×5 mlice-cold buffer. The amount of radioactivity on the filters isdetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding.

In vitro Inhibition of ³H-Epibatidin Binding

Epibatidin is an alkaloid that was first isolated from the skin of theEcuadoran frog Epipedobates tricolor and was found to have very highaffinity for neuronal nicotinic receptors, where it acts as a potentagonist. 3H-epibatidin binds to two sites in rat brain, both of whichhave pharmacological profiles consistent with neuronal nicotinicreceptors and a similar brain regional distribution (Hougling et al.,Mol. Pharmacol. 48, 280-287 (1995)).

The high affinity binding site for ³H-epibatidin is most certainlybinding to the α₄β₂ subtype of nicotinic receptors. The identity of thelow affinity site is still unknown; does it represent a second nicotinicreceptor or a second site in the same receptor. The inability ofα-bungarotoxin to compete for ³H-epibatidin binding sites indicates thatneither site measured represents the nicotinic receptor composed of α₇subunits.

Tissue preparation: Preparations are performed at 0-4° C. unlessotherwise indicated. The forebrain (÷cerebellum) from a male Wistar rat(150-250 g) is homogenised for 10-20 sec in 20 ml Tris, HCl (50 mM, pH7.4) using an Ultra-Turrax homogeniser. The tissue suspension iscentrifuged at 27,000×g for 10 min. The supernatant is discarded and thepellet is washed three times by centrifugation at 27,000×g for 10 min in20 ml fresh buffer, and the final pellet is resuspended in fresh buffer(400 ml per g of original tissue) and used for binding assays.

Assay: Aliquots of 2.0 ml homogenate are added to 0.100 ml of testsolution and 0.100 ml of ³H-epibatidin (0.3 nM, final concentration),mixed and incubated for 60 min at room temperature. Non-specific bindingis determined using (−)-nicotine (30 μM, final concentration). Afterincubation the samples are poured directly onto Whatman GF/C glass fibrefilters (presoaked in 0.1% PEI for at least 20 min) under suction andimmediately washed with 2×5 ml ice-cold buffer. The amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

Results are given as IC₅₀ values; the concentration (μM) that inhibitbinding of the radioactive ligand by 50%.

Below test results for one compound of the invention are presented:

(The Compound Numbers Refers to the Examples.)

³H-cytisine ³H-epibatidin ³H-α-bungarotoxin Compound IC₅₀ (μM) IC₅₀ (μM)IC₅₀ (μM) 1a 0.023 0.0840 0.500 2a 0.0220 0.0800 0.550 3a 1.300 8.0001.440 4a 2.700 6.300 3.500 5b 0.020 0.091 1.900 2c 63.80 367.0 0.100 3c17.0 >10.0 0.640 4c 0.030 0.200 0.440 1d 120.000 450.000 0.170 2d110.000 310.000 0.0670 1e >10.0 >10.0 0.800 3e >10.0 >10.0 0.5100 1f2.200 2.800 0.082 2f 30.0 >10.0 1.300

PHARMACEUTICAL COMPOSITIONS

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers and/ordiluents.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefor and,optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, nasal, topical (including buccal and sub-lingual),transdermal, vaginal or parenteral (including intramuscular,sub-cutaneous and intravenous) administration, or those in a formsuitable for administration by inhalation or insufflation.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the chemical compoundaccording to the invention may be formulated as ointments, creams orlotions, or as a transdermal patch. Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilising agents, dispersing agents,suspending agents, thickening agents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size forexample of the order of 5 microns or less. Such aparticle size may be obtained by means known in the art, for example bymicronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired. It is presently contemplated that compositions containing offrom about 0.1 to about 500 mg of active ingredient per unit dosage,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

A satisfactory result can, in certain instances, be obtained at a dosageas low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of thedosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred rangesare from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about10 mg/kg p.o.

METHOD OF TREATING

The compounds of the present invention are valuable nicotinic AChreceptor modulators and therefore useful for the treatment of a range ofailments involving cholinergic dysfunction as well as a range ofdisorders responsive to the activity of nicotinic ACh receptormodulators. The compounds may be used in the treatment, prevention,profylaxis or alleviation of a disease, disorder or condition of thecentral nervous system as for example: neurodegenerative disorders,cognitive or memory dysfunction, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles dela Tourettes syndrome, attention deficit hyperactivity disorder,anxiety, depression, mania, manic depression, schizophrenia, obsessivecompulsive disorders, eating disorders like anorexia nervosa, bulimiaand obesity, narcolepsy, nociception, memory loss, memory dysfunction,AIDS-dementia, senile dementia, peripherial neuropathy, leaming deficit,cognition deficit, attention deficit, autism, dyslexia, tardivedyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome,social phobia, chronic fatigue syndrome, disorders of sleep,pseudodementia, Ganser's syndrome, prementraul syndrome, late lutealphase syndrome, chronic fatigue syndrome, premature ejaculation,erectile difficulty, mutism and trichotillomania.

The compounds of this invention may also be used in the treatment ofinflammatory conditions as for example: inflammatory skin conditionslike acne and rosacea, Chron's disease, inflammatory bowel disease,ulcerative collitis, diarrhoea.

Also the compounds of the invention may be used in the treatment ofdiseases associated with smooth muscle contractions as for example:convulsive disorders, angina pectoris, premature labor, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

The compounds of this invention may also be used in the treatment ofpain as for example chronic, acute and recurrent pain, postoperativepain, migraine pain or phantom limb pain;

The compounds of the present invention may also be used for theassistance in cessation of abuse of chemical substances as for examplesmoking cessation as well as cessation of use of other nicotinecontaining products, cessation of use of opiods like heroin, cocaine andmorphine and cessation of use of benzodiazepines or alcohol. In thecontext of the present invention “treatment” means as well treatment asprevention, profylaxis and alleviation of withdrawal symptoms andabstinence as well as treatment resulting in a voluntary diminishedintake of the addictive substance.

Suitable dosage range are 0.1-500 milligrams daily, and especially 10-70milligrams daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

I.p. means intraperetoneally, which is a well known route ofadministration.

P.o. means peroral, which is a well known route of administration.

The following examples will illustrate the invention further, however,they are not to be construed as limiting.

EXAMPLES

General: All reactions involving air sensitive reagents or intermediateswere performed under nitrogen and in anhydrous solvents. Magnesiumsulfate was used as drying agent in the workup-procedures and solventswere evaporated under reduced pressure.

Method A 1a: (±)-8-Benzyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a mixture of 3-bromopyridine (11.0 g, 69.7 mmol) and diethyl ether(200 ml), butyllithium in hexanes (2.5 M, 30.7 ml, 76.7 mmol) was addedat −70° C. The mixture was stirred at −70° C. for 1 h.8-benzyl-8-azabicyclo[3.2.1]octan-3-one (15.0 g, 69.7 mmol) solved indiethyl ether (80 ml) was added at −70° C. and stirred for 1 h. Thereaction mixture was allowed to warm to room temperature overnight.Aqueous sodium hydroxide (1 M, 200 ml) was added and the diethyl etherwas separated. The water phase was extracted three times with ethylacetate (100 ml). The organic phases were mixed.Endo-8-benzyl-3-hydroxy-3-(3-pyridyl)-8-azabicyclo[32.1]octane wasisolated after trituration with petroleum ether. Yield 7.0 g, 34%. Amixture ofendo-8-benzyl-3-hydroxy-3-(3-pyridyl)-8-azabicyclo[3.2.1]octane (3.0 g,10.2 mmol), thionyl chloride (9 ml, 123 mmol) and tetrahydrofuran (100ml) was stirred at 50° C. for 0.5 h. The mixture was evaporated andcombined with potassium hydroxide (4.6 g, 82.0 mmol), ethanol (25 ml)and water (25 ml) and stirred for 5 min. The ethanol was evaporated andwater (50 ml) was added, followed by extraction twice with ethyl acetate(50 ml). Chromatography on silica gel with dichloromethane, methanol andconc. ammonia (89:10:1) gave the free base of title compound yield 2.2g, 78%. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Mp142-146° C.

2a:(±)-8-Methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene Fumaric AcidSalt

Prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one according tomethod a.

Mp 124-126° C.

3a:(±)-8-Methyl-3-(3-quinolinyl)-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

Prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one according tomethod a. Mp 140.8-143.8° C.

4a:(±)-3-(3-Benzofuryl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

Prepared according to method a. Mp 140.9-142.8° C.

5a:(±)-3-(3-Benzothienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

Prepared according to method a. Mp 146.6-149.5° C.

6a:(±)-3-(2-Thiazolyl)-8-Methyl-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

Prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one according tomethod a

Mp 196.3-198.5° C.

7a:(±)-8-Methyl-3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

Prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one according tomethod a.

8a:(±)-8-Methyl-3-(3-thienyl)-8-azabicyclo[3.2.1]oct-2-ene HydrochloricAcid Salt

Prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one according tomethod a

Mp 117-118.5° C.

9a:(±)-8-Methyl-3-(2-naphtyl)-8-azabicyclo[3.2.1]oct-2-ene HydrochloricAcid Salt

Prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one according tomethod a; Mp 259-264° C.

10a:Exo-8-Methyl-3-(3-pyridyl)-8-azabi cyclo[3.2.1]octaneDihydrochloride

A mixture of endo andexo3-hydroxy-8-Methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]octane (method a)(1.5 g, 6.9 mmol), Raney nickel (20.0 g, 50% slurry in water) and 50 mlethanol was stirred under reflux for 15 h. The crude mixture wasfiltered followed by chromatography an silica gel with dichioromethane,methanol and conc. ammonia (89:10:1) gave the product as free base. Theproduct was converted to the title compound by addition of hydrochloridein ethanol. Mp 275-280° C. Yield 0.55 g, 29%.

11a:Endo-3-hydroxy-3-(3-pyridyl)-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octane

A mixture ofendo-8-benzyl-3-hydroxy-3-(3-pyridyl)-8-azabicyclo[3.2.1]octane (3.0 g,10.2 mmol), palladium on carbon (5%, 0.80 g), concentrated hydrochloricacid (2 ml) and ethanol (75 ml) was stirred under hydrogen for 15 h. Thecrude mixture was filtered through celite and evaporated to dryness andstirred with triethylamine (4.1 g, 40.0 mmol),di-(tertbutoxycarbonyl)anhydride (1.75 g, 8.0 mmol) and dichloromethane(50 ml) for 3.5 hours. The crude mixture was evaporated followed bychromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) which gave the title compound. Mp 90-92° C., yield 2.8g, 90%.

12a:(±)-3-(3-Pyridyl8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene

A mixture ofEndo-3-hydroxy-3-(3-pyridyl)-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octane2.0 g, 6.6 mmol), thionyl chloride (6 ml, 82 mmol) and tetrahydrofuran(100 ml) was stirred at 50° C. for 0.5 h. The mixture was evaporated andcombined with potassium hydroxide (3.0 g, 53 mmol), ethanol (20 ml) andwater (20 ml) and stirred for 10 min. The ethanol was evaporated andwater (50 ml) was added. The mixture was extracted twice with ethylacetate (50 ml). Chromatography on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound as an oil.Yield 0.43 g, 23%.

Method B 1b:(±)-8-H-3-(3-Pyridyl8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

(±)-3-(3-Pyridyl)-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene(0.40 g, 1.40 mmol stirred in a mixture of trifluoroacetic acid (3.2 g,28 mmol) and dichloromethane overnight. Aqueous sodium hydroxide (100ml, 1 M) was added followed by extraction with dichloromethane (100 ml)three times. Chromatography on silica gel with dichloromethane, methanoland conc. ammonia (89:10:1) gave the title compound pure. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Yield 0.13 g, 31%.Mp 175-176° C.

2b:(±)-8-Methyl-3-trifluoramethanesulfonyl-oxy-8-azabicyclo[3.2.1]oct-2-ene

To 8-methyl-8-azabicyclo[3.2.1]octan-3-one (12.65 g, 90.9 mmol) intetrahydrofuran (300 ml), was added at −70° C.; sodiumbis(trimethylsilyl)amide in tetrahydrofuran (77.5 ml, 77.5 mmol).

The reaction mixture was stirred for 30 min at −70° C.N-phenylbis(trifluoromethane-sulfonamide) (32.5 g, 90.9 mmol) intetrahydrofuran (200 ml) was added at −70° C. The reaction mixture wasallowed to reach room temperature slowly and was stirred over night.Aqueous sodium hydroxide (0.1 M, 500 ml) was added and the mixture wasextracted twice with ethyl acetate (200 ml). Chromatography on silicagel with dichloromethane and 10% ethanol as solvent gave the titlecompound as an oil. Yield 16.2 g, 45%.

3b:(±)-8-Methyl-3-[3-(6-methoxy)pyridyl]-8-azabicyclo[3.2.1]oct-2-ene

A mixture of(±)-8-Methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo[3.2.1]oct-2-ene(3.0 g 12.2 mmol), hexamethyiditin (4.0 g, 12.2 mmol),bis(triphenylphosphine)palladium(II)-dichloride (0.43 g, 0.61 mmol) andlithium chloride (0.52 g, 12.3 mmol) was stirred in 1.4-dioxane (25 ml)at 70° C. for 2 h. Then 3-Bromo-6-methoxypyridine (4.6 g, 24.4 mmol) wasadded followed by stirring at reflux overnight. The solvent wasevaporated and aqueous sodium hydroxide (30 ml, 1 M) was added followedby extraction three times with ethyl acetate is (30 ml). Chromatographyon silica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound as an oil. Yield 1.0 g, 36%.

4b:(±)-3-Acetyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene Fumaric Acid Salt

A mixture of(±)-8-Methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo[3.2.1]oct-2-ene(2.0 g, 7.4 mmol), 1-methoxy-1-trimethylstannylethylene (2.45 g, 11.1mmol), bis(triphenylphosphine)palladium(II)-dichloride (0.26 g, 0.37mmol) and lithium chloride (0.31 g, 7.4 mmol) was stirred intetrahydrofuran (30 ml) at reflux overnight. The solvent was evaporated.Sodium hydroxide (40 ml, 1 M) was added and the mixture was extractedwith ethyl acetate. Mp 148.5-150° C. Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave(±)-3-(1-methoxy-1-ethenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt (0.23 g, 17%) which was mixed with hydrogen chloridein methanol (10 ml, 4.5 M) and stirred for 10 min. The mixture wasevaporated to dryness and sodium ethoxide (0.19 g, 8.4 mmol) was added.Chromatography of this crude mixture on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Yield 0.21 g, 58%.Mp 175-176° C.

5b:(±)-8-Methyl-3-[3-(6-chloro)pyridyl]-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

A mixture of(±)-8-Methyl-3-3-(6-methoxy)pyridyl]-8-azabicyclo[3.2.1]oct-2-ene (0.50g, 2.13 mmol) and phosphorus oxychloride (4 ml) in dimethylformamide (5ml) was stirred overnight at 95° C. Ice (100 g) and aqeous sodiumhydroxide (4 M, 50 ml) was added followed by extraction three times withethyl acetate (50 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as an oil. The corresponding salt was obtained by addition of adiethyl ether and methanol mixture (9:1), saturated with fumaric acid.Yield 0.35 g, 47%. Mp 140-142° C.

6b:(±)-8-Methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo[3.2.1]oct-2-ene

To 8-methyl-8-azabicyclo[3.2.1]octan-3-one (9.35 g, 67.2 mmol) intetrahydrofuran, was added at −70° C.: sodium bis(trimethylsilyl)amidein tetrahydrofuran (73.9 ml, 73.9 mmol). The reaction mixture wasstirred for 10 min. N-phenylbis(trifluoromethanesulfonamide) (24.0 g,67.2 mmol) in tetrahydrofuran was added at −70° C. The reaction mixturewas allowed to reach room temperature slowly and was stirred over night.Aqueous sodium hydroxide (0.1 M, 350 ml) was added and the mixture wasextracted twice with 150 ml ethyl acetate. Chromatography on silica gelwith dichloromethane and 10% ethanol as solvent gave the title compoundas a brown oil. Yield 11.6 g, 70%.

Method C 1c:(±)-3-(2-Benzofuryl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

A mixture of(±)-8-Methyl-3-trifluoromethanesulfonyl-oxy-B-azabicyclo[3.2.1]oct-2-ene(1.5 g 6.1 mmol), benzofuran-2-boronic acid (0.99 g, 6.1 mmol),tetrakis(triphenyl-phosphine)-palladium(0) (0.07 g, 0.06 mmol) andlithium chloride (0.26 g, 6.1 mmol), potassium carbonate (4.2 g, 30.5mmol), water (15 ml) and 1,2-dimethoxyethane (15 ml) was refluxed for1.5 h. Water (50 ml) was added and the mixture was extracted twice withethyl acetate (50 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1), saturated with fumaric acid. Yield0.24 g, 11%. Mp 188.3-190.9° C.

2c:(±)-3-(2-Benzothienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2ene

Prepared according to method c. Mp 81.0-83.6° C.

3c:(±)-3-(3-Acetamidophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared according to method c from 3-acetamidobenzeneboronic acid. Mp195.3-196.9° C.

4c:(±)-3-(3-Aminophenyl) 8-methyl-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

A mixture of(±)-3-(3-Acetamidophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (0.32 g,1.25 mmol) and hydrochloric acid (25 ml, 25%) was stirred at refluxovernight. The mixture was evaporated to dryness. Aqueous sodiumhydroxide (1 M, 50 ml) was added and the mixture was extracted twicewith ethyl acetate (50 ml) Mp 195.3-196.9° C. Yield 0.22 g, 52%.

Method D 1d:(±)-3-(2-Benzofuryl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a mixture of benzofuran (20.0 g, 169.3 mmol) and diethyl ether (200ml), butyllithium in hexanes (2.5 M, 75 ml, 186 mmol) was added at 0° C.The mixture was stirred at 0° C. for 0.5 h and then cooled to −70° C.8-benzyl-8-azabicyclo[3.2.1]octan-3-one (23.0 g, 169.3 m solved indiethyl ether (150 ml) was added at −70° C. and stirred for 1 h. Thereaction mixture was allowed to warm to room temperature ovemight. Water(200 ml) was added and endo andexo-3-(2-benzofuryl)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane wasisolated by filtration. Yield 38.7 g, 89%. A mixture of endo andexo-3-(2-benzofuryl)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane (30.0g, 116.6 mmol), conc. hydrochloric acid (35 ml) and ethanol (300 ml) wasstirred at reflux for 1 h. The solvent was evaporated. Sodium hydroxide(150 ml, 4M) was added and the mixture was extracted twice with ethylacetate (100 ml).(±)-3-(2-benzofuranyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene wasisolated, yield 18.9 g, 70%. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1), saturated withfumaric acid. Mp 188.5-191.2° C.

2d:(±)-3-(2-Benzothienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneHydrochloride

Prepared according to method d. Mp>250° C.

3d:(±)-3-(2-Thienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene Fumaric AcidSalt

Prepared according to method d. Mp 141.5-143.5° C.

4d:(±)-3-[2-(3-Methoxymethylthienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene

Prepared according to method d. Isolated as an oil.

5d:(±)-3-(2-Benzothiazolyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared according to method d. Mp 195-196.8° C.

6d:(±)-3-[2-(1-Methylindolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared according to method d, with exception of the metalationtemperature, at reflux and 1.2 eqv. of tetramethylethylenediamine.

7d:(±)-3-(2-Furyl)-8-methyl-8azabicyclo[3.2.1]oct-2-ene

Prepared according to method d. Isolated as an oil.

8d:(±)-3-(2-Thieno[3.2-b]thienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneOxalic Acid Salt

Prepared according to method d. Mp 48-50° C.

9d:(±)-3-(2-Thieno[2.3-b]thienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneOxalic Acid Salt

Prepared according to method d. Mp 46-48° C.

10d:(±)-3-(2-selenophenyl)8-methyl-8-azabicyclo[3.2.1]oct-2-ene

Prepared according to method d. Mp 176.8-178.3° C.

Method E 1e:(±)-3-(2-Benzofuryl)-8-H-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

A mixture of (±)-3-(2-Benzofuryl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene(5.4 g, 22.6 mmol), 1-chloroethylchloroformate (5.0 g, 34.7 mmol) andxylen (25 ml) was stirred at reflux overnight. Methanol was added andthe mixture was stirred 2h at reflux. Sodium hydroxide (4 M, 50 ml) wasadded at room temperature and the mixture was extracted with ethylacetate. Chromatography on silica gel with dichloromethane, methanol andconc. ammonia (89:10:1) gave the title compound. The corresponding saltwas obtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 2.58 g, 33%. Mp 201-204° C.

2e:(±)-3-[3-(3-Furyl)-2-thienyl]-8-H-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared from(±)-3-[3-(3-furyl)-2-thienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneaccording to method E. Mp 187-189° C.

3e:(±)-3-(2-Benzofuryl)-8ethyl-8-azabicyclo[3.2.1]oct-2-ene Fumaric AcidSalt

A mixture of (±)-3-(2-Benzofuryl)-8-H-8-azabicyclo[3.2.1]oct-2-ene (1.5g, 6.7 mmol), bromoethane (0.80 g, 7.3 mmol), diisopropylethylamine(0.87 g, 6.7 mmol) and DMF (50 ml) was stirred for 2h. Sodium hydroxide(100 ml, 1 M) was added followed by extraction twice with diethylether(100 ml). Chromatography on silica gel with dichloromethane, methanoland conc. ammonia (89:10:1) gave the title compound. The correspondingsalt was obtained by addition of a diethyl ether and methanol mixture(9:1), saturated with fumaric acid. Yield 0.77 g, 31%. Mp 197-203° C.

Method F1f:(±)-3-[2-(3-bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a solution of 3-bromothiophene (25.0,153.3 mmol) in THF (250 ml) wasadded: lithiumdiisopropylamide (2 M, 168.7 mmol) at −80° C. The mixturewas stirred for 1 h at −80° C. followed by addition of tropinone (21.3g, 153.3 mmol) in THF (200 ml). The mixture was stirred at −80° C. for 1h and was allowed to reach roomtemperature overnight. Sodium hydroxide(1 M, 200 ml) was added and extracted three times with diethylether (300ml). Chromatography on silica gel with dichloromethane, methanol andconc. ammonia (89:10:1) gave endo andexo-3-[3-bromo-(2-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane.

Yield 8.90 g, 19%.

A mixture of endo andexo-3-[3-bromo-(2-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane(8.85 g, 29.3 mmol) and concentrated hydrochloric acid was stirred for 2h. The hydrochloric acid was evaporated and sodium hydroxide (1 M, 200ml) was added and the mixture was extracted twice with ethyl acetate(100 ml). Yield 8.3 g, 100%. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1), saturated withfumaric acid. Mp 130-132° C.

2f:(±)-3-[2-(3-Bromobenzofuryl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared according to method F. Mp 161.4-163.3° C.

3f:(±)-3-[2-(3-Bromobenzothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared according to method F. Mp 165.0-166.9° C.

4f:(±)-3-[2-(3-Chlorothienyl)]8-methyl-B-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

Prepared according to method F. Mp 151.5-153.5° C.

5f:(±)-3-[3-(3-Furyl)-2-thienyl]-8-methyl-8azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

A mixture of(±)-3-[2-(3-bromothienyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene (2.0 g,7.0 mmol), 3-furylboronic acid (0.94 g, 8.4 mmol),tetrakis(triphenylphosphine)-palladium(0) (0.16 g, 0.14 mmol), aqueouspotassium carbonate (10.5 ml, 2 M), 1,3-propanediol (2.66 g, 35 mm ol),1,2-dimethoxyethane (30 ml) and dioxane (50 ml) was stirred at refluxovernight. Sodium hydroxide (50 ml) was added and the mixture wasextracted twice with ethyl acetate (50 ml). Chromatography on silica gelwith dichloromethane, methanol and conc. ammonia (89:10:1) gave thetitle compound. The corresponding salt was obtained by addition of adiethyl ether and methanol mixture (9:1) saturated with fumaric acid.Yield 1.59 g, 59%. Mp 187-189° C.

What is claimed is:
 1. An 8-azabicyclo[3.2.1]oct-2-ene compound of Formula 1,

any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically acceptable salt thereof; wherein R is hydrogen, C₁₋₆-alkyl, phenyl, or benzyl; and

wherein R² is hydrogen or C₁₋₆-alkyl; or furanyl, thienyl, oxazolyl, isoxazolyl, pyridyl, or thiazolyl, which heteroaryl group is optionally substituted one or more times with substituents selected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, CF₃, OCF₃, CN, nitro and furyl.
 2. The 8-azabicyclo[3.2.1]oct-2-ene compound of claim 1, wherein R is hydrogen, methyl, ethyl or benzyl; and R¹ is acetyl, 3-pyridyl, 3-(6-methoxy)pyridyl, 3-(6-chloro)pyridyl, 2-thiazolyl, 3-thienyl, 2-thienyl, 2-(3-methoxymethyl)thienyl, 2-furyl, 3-furyl, 2-(3-bromo)thienyl), 3-chloro-thien-2-yl or 3-(3-furyl)-2-thienyl.
 3. The 8-azabicyclo[3.2.1]oct-2-ene compound of claim 1, which is (±)-8-Methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-(2-Thiazolyl)-8-Methyl-8-azabicyclo[3.2.1]oct-2-ene; (±)-8-Methyl-3-(3-thienyl)-8-azabicyclo[3.2.1]oct-2-ene; Exo-8-Methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]octane; (±)-8-H-3-(3-Pyridyl)-8-azabicyclo[3.2.1]oct-2-ene; (±)-8-Methyl-3-[3-(6-methoxy)-pyridyl)]-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-Acetyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; (±)-8-Methyl-3-[3-(6-chloro)-pyridyl]-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-(2-Thienyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-(2-Furyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-[3-(3-Furyl)-2-thienyl]-8-H-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; (±)-3-[2-(3-Bromobenzothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; 3-[2-(3-Chlorothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or (±)-3-[3-(3-Furyl)-2-thienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or a pharmaceutically acceptable addition salt thereof.
 4. A method for the preparation of the 8-azabicyclo[3.2.1]oct-2-ene compound according to claim 1, which method comprises: a) the step of reacting a compound having the formula

wherein R is as defined above, with a compound of formula R¹—X, wherein R¹ is as defined in claim 1, and X is halogen, boronic acid, or trialkylstannyl; or b) the step of reducing a compound having the formula

wherein R¹ is as defined in claim
 1. 5. A method of treating a human being or animal suffering from chemical substance addiction comprising administering to said human being or animal in need thereof a therapeutically effective amount of the 8-azabicyclo[3.2.1]oct-2-ene compound of any one of claims 1, 2, or
 3. 6. The method according to claim 5, wherein the chemical substance is tobacco. 